双语综述|造影剂诱发的急性肾损伤的定义、发病机制、危险因素、预防和治疗的评价

【编者按】最近，来自重庆的药学和放射科同道在BMC Nephrology上发表了关于造影剂引起急性肾损伤的详细综述，小崔医生整理成了双语对照，供愿意看英文的同道学习，如果想快速了解知识，可以看中文部分。

BMC Nephrol 2024 Apr 22;25(1):140

Contrast-induced acute kidney injury: a review of definition, pathogenesis, risk factors, prevention and treatment          

造影剂诱发的急性肾损伤的定义、发病机制、危险因素、预防和治疗的评价

Contrast-induced acute kidney injury (CI-AKI) has become the third leading cause of hospital-acquired AKI, which seriously threatens the health of patients. To date, the precise pathogenesis of CI-AKI has remained not clear and may be related to the direct cytotoxicity, hypoxia and ischemia of medulla, and oxidative stress caused by iodine contrast medium, which have diverse physicochemical properties, including cytotoxicity, permeability and viscosity. The latest research shows that microRNAs (miRNAs) are also involved in apoptosis, pyroptosis, and autophagy which caused by iodine contrast medium (ICM), which may be implicated in the pathogenesis of CI-AKI. Unfortunately, effective therapy of CI-AKI is very limited at present. Therefore, effective prevention of CI-AKI is of great significance, and several preventive options, including hydration, antagonistic vasoconstriction, and antioxidant drugs, have been developed. Here, we review current knowledge about the features of iodine contrast medium, the definition, pathogenesis, molecular mechanism, risk factors, prevention and treatment of CI-AKI.          

造影剂诱发的急性肾损伤（CI-AKI）已成为医院获得性AKI的第三大病因，严重威胁患者的健康。迄今为止，CI-AKI的确切发病机制尚不清楚，可能与碘造影剂引起的直接细胞毒性、髓质缺氧缺血和氧化应激有关，碘造影剂具有多种理化性质，包括细胞毒性、渗透性和粘度。最新研究表明，microRNA（miRNA）也参与碘造影剂（ICM）引起的细胞凋亡、细胞焦亡和自噬，这可能与CI-AKI的发病机制有关。不幸的是，目前CI-AKI的有效治疗非常有限。因此，有效预防CI-AKI具有重要意义，已经开发了几种预防选择，包括补液、拮抗血管收缩和抗氧化药物。在这里，我们回顾了目前关于碘造影剂的特征、定义、发病机制、分子机制、危险因素、预防和治疗CI-AKI的知识。

Contrast agents are injected into the body through blood vessels in order to change the image contrast of local tissues, enhance the development effect, as well as improve disease diagnosis and treatment. In recent years, with the extensive application of computed tomography CT in clinical diagnosis, iodine-containing contrast agents also known as iodine contrast medium (ICM) have become an indispensable part of disease diagnosis and have been widely used in clinical [1]. However, some studies have shown that 11–40% of patients with iodine contrast medium will develop acute kidney injury (AKI), that is, contrast-induced acute kidney injury (CI-AKI) or contrast induced nephropathy (CIN) [2, 3]. With in-depth research on the relationship between ICM and AKI, the term CIN has become less commonly used. CIN was a historic definition, replaced by CI-AKI, the term endorsed by Kidney Disease: Improving Global Outcomes (KDIGO) [4].     

造影剂通过血管注射到体内，以改变局部组织的图像对比度，增强显影效果，改善疾病的诊断和治疗。近年来，随着计算机断层扫描CT在临床诊断中的广泛应用，含碘造影剂（也称为碘造影剂（ICM）已成为疾病诊断中不可或缺的一部分，并在临床上得到了广泛的应用[1]。然而，一些研究表明，11%-40%的碘造影剂患者会发生急性肾损伤（AKI），即造影剂诱导的急性肾损伤（CI-AKI）或造影剂诱发的肾病（CIN）[2,3]。随着对ICM与AKI之间关系的深入研究，CIN一词已变得不那么常用。CIN是一个历史性的定义，被CI-AKI所取代，CI-AKI是肾脏疾病：改善全球结局（Kidney Disease：Improving Global Outcomes， KDIGO）认可的术语[ 4]。   

In order to distinguish and clarify the relationship between ICM and AKI, the European Society of Urogenital Radiology (ESUR) [5] and the American College of Radiology(ACR) [6]proposed the terms post-contrast kidney injury (PC-AKI), CI-AKI, and contrast-associated acute kidney injury (CA-AKI). The term PC-AKI is used to describe a decrease in renal function that follows intravascular administration of ICM within 48 h. CA-AKI: Any AKI occurring within 48 h after the administration of contrast media. The term PC-AKI is synonymous with CA-AKI and appears inradiology guidelines [6].Both terms imply correlative diagnosis. Neither term implies a causal relationship between contrast medium administration and an AKI event.CI-AKI is the subset of PC-AKI or CA-AKI that can be causally linked to contrast media administration. When it is clear that there is a causal relationship between ICM and AKI, it is recommended to use CI-AKI [5]. This review adopts the term CI-AKI.     

为了区分和阐明ICM与AKI之间的关系，欧洲泌尿生殖放射学会（ESUR）[5]和美国放射学会（ACR）[6]提出了造影剂后肾损伤（PC-AKI）、CI-AKI和造影剂相关急性肾损伤（CA-AKI）这几个术语。术语 PC-AKI 用于描述在 48 小时内血管内施用 ICM 后肾功能下降。CA-AKI：在造影剂给药后 48 小时内发生的任何 AKI。术语PC-AKI是CA-AKI的同义词，出现在放射学指南中[ 6]。这两个术语都意味着相关的诊断。这两个术语都不意味着造影剂给药与AKI事件之间的因果关系。CI-AKI 是 PC-AKI 或 CA-AKI 的子集，可能与造影剂给药有因果关系。当ICM和AKI之间有因果关系时，建议使用CI-AKI [ 5]。本综述采用术语CI-AKI。

CI-AKI has become a leading cause of hospital-acquired AKI affecting the health of patients in China. Hydration therapy was once considered the most convenient, effective, and economical method for preventing CI-AKI. Therefore, the 2012 KDIGO AKI Clinical Practice Guidelines [7] and the 2018 ESUR CI-AKI Prevention and Treatment Guidelines [8] both recommend the use of hydration therapy for the prevention of CI-AKI. Unfortunately,, there is currently no specific treatment for CI-AKI. Many randomized controlled trials (RCTs) and meta-analyses have analyzed various drugs such as N-acetylcysteine(NAC), statins, sodium glucose cotransporter 2 inhibitors (SGLT2i) and vitamin C, but there is no clear evidence to suggest that they can reduce the risk of CI-AKI [8, 9]. Effective treatment of CI-AKI is very limited at present. Therefore, the mechanisms underlying the occurrence and progression of CI-AKI have attracted much research attention in recent years. In this review, we highlight recent advances in our knowledge of CI-AKI pathogenesis, potential molecular mechanisms, risk factors, prevention and treatment of CI-AKI.          

CI-AKI已成为影响中国患者健康的医院获得性AKI的主要原因。补液疗法曾被认为是预防CI-AKI最方便、最有效和最经济的方法。因此，2012 年 KDIGO AKI 临床实践指南 [ 7] 和 2018 年 ESUR CI-AKI 预防和治疗指南 [ 8] 都建议使用水化疗法来预防 CI-AKI。不幸的是，目前还没有针对 CI-AKI 的特异性治疗方法。许多随机对照试验（randomized controlled trials， RCTs）和meta分析分析了各种药物，如N-乙酰半胱氨酸（NAC）、他汀类药物、钠葡萄糖协同转运蛋白2抑制剂（SGLT2i）和维生素C，但没有明确的证据表明它们可以降低CI-AKI的风险[8,9]。目前CI-AKI的有效治疗非常有限。因此，CI-AKI发生发展的机制近年来备受研究关注。在这篇综述中，我们重点介绍了我们在CI-AKI发病机制、潜在分子机制、危险因素、预防和治疗CI-AKI方面的最新进展。

With the continuous advances of imaging technology, iodine contrast medium have been widely used in clinical diagnostic techniques, such as CT, commonly used for CT angiography and CT perfusion. And body cavity, joint, spinal cord imaging due to their abilities to improve the detection rate of lesion sites as well as facilitate lesion localization, qualitative and differential diagnosis [5]. The structure of iodine contrast medium used currently in clinical is a benzenic ring carrying three iodine ions, that is, one iodine ion is replaced in the 1, 3, 5 position of the benzenic ring, and the 2, 4, 6 position can bind three side chains, which together form a triiodobenzene ring derivative. According to the lonization state in solution, they can be divided into ionic and non-ionic contrast agents. As for non-ionic contrast agents, the non-ionic hydrophilic hydroxyl group is distributed around the benzene ring, shielding the hydrophobic iodophenyl group in it, thereby increasing the water solubility of the compound and reducing its toxicity [10]. Based on the size of plasma osmotic concentration, iodine contrast medium can be divided into high-osmolal, low-osmolal, and iso-osmolal ICM. The osmotic concentration of high-osmolal ICM is more than five times that of plasma osmotic; low-osmolal ICM is about two-three times that of plasma osmotic concentration (600–800 mmol/L); the osmotic concentration of iso-osmolal ICM is roughly the same as that of plasma osmotic concentration (about 290 mmol/L). According to the number of the benzene ring in the chemical structure, they can be divided into haplotype and dimer iodine contrast medium. Haplotype iodine contrast medium have only three iodine ions; the dimer iodine contrast medium are formed by connecting two triiodobenzene rings; thus, at the same iodine content, the dimer iodine contrast medium exhibit fewer molecule number, lower penetration concentration, and higher viscosity than the haplotype iodine contrast medium [11]. The details of iodine contrast medium are provided in Table 1.        

随着成像技术的不断进步，碘造影剂已广泛应用于临床诊断技术，如CT，常用于CT血管造影和CT灌注。以及体腔、关节、脊髓成像，因为它们能够提高病变部位的检出率，并促进病变定位、定性和鉴别诊断[5]。目前临床上使用的碘造影剂结构是携带三个碘离子的苯环，即在苯环的1、3、5位置换一个碘离子，而2、4、6位可以结合三条侧链，共同形成三碘苯环衍生物。根据溶液中的离子状态，它们可分为离子造影剂和非离子造影剂。至于非离子造影剂，非离子亲水羟基分布在苯环周围，屏蔽其中的疏水性碘苯基，从而增加化合物的水溶性并降低其毒性[10]。根据血浆渗透浓度的大小，碘造影剂可分为高渗透压、低渗透压和等渗透压ICM。高渗透压ICM的渗透浓度是血浆渗透的5倍以上;低渗透压ICM约为血浆渗透浓度（600-800 mmol/L）的2-3倍;等渗透压ICM的渗透浓度与血浆渗透浓度大致相同（约290 mmol/L）。根据苯环在化学结构中的数目，可分为单倍型和二聚碘造影剂。单倍型碘造影剂只有三个碘离子;二聚碘造影剂由连接两个三碘苯环形成;因此，在相同的碘含量下，二聚碘造影剂比单倍型碘造影剂表现出更少的分子数、更低的渗透浓度和更高的粘度[11]。碘造影剂的详细信息见表1。   

CI-AKI was first defined by the European Society of Urogenital Radiology (ESUR) in 2002: in the absence of surgery, nephrotoxic drugs and other factors, serum creatinine (Scr) content increased by 25% or 44.2 µmol/L compared with the baseline value within 72 h after intravascular administration of iodine contrast medium [12]. According to the updated 2011 ESUR Contrast Media Safety Committee guidelines, clinical CI-AKI is defined as the notion that without the influence of surgery, nephrotoxic drugs, and other causes, renal function is impaired, and Scr content is increased by 0.5 mg/dL (44.2 µmol/L) or more than 25% compared with the basic value within 72 h after intravascular injection of iodine contrast medium [13]. Although the KDIGO used the CI-AKI in 2012, it is defined as an absolute increase of 26.5 µmol/L in Scr content compared to baseline within 48 h after intravascular administration of iodine contrast medium, or a relative increase of more than 50% within 7 days, without the influence of factors such as surgery or nephrotoxic drugs [14]. The specialist consensus for CI-AKI in China indicates that exclusion of other factors, Scr levels increased by 25% or 0.5 mg/dL compared to the baseline value after use of contrast agents [15].          
2002年，欧洲泌尿生殖放射学会（European Society of Urogenital Radiology， ESUR）首次定义了CI-AKI：在没有手术、肾毒性药物和其他因素的情况下，血管内给予碘造影剂后72 h内，血清肌酐（scr）量比基线值增加25%或44.2 μmol/L[12]。根据2011年ESUR造影剂安全委员会更新的指南，临床CI-AKI被定义为在没有手术、肾毒性药物和其他原因的影响下，肾功能受损，Scr含量比血管内注射碘造影剂后72 h内的基本值增加0.5mg/dL（44.2μmol/L）或25%以上[13]。尽管KDIGO在2012年使用了CI-AKI，但其定义为在血管内给予碘造影剂后48小时内，与基线相比，Scr含量绝对增加26.5μmol/L，或在7天内相对增加50%以上，不受手术或肾毒性药物等因素的影响[14]。中国CI-AKI的专家共识表明，排除其他因素后，使用造影剂后，Scr水平比基线值增加25%或0.5mg/dL[15]。 

Approximately 13.3 million patients worldwide are diagnosed with AKI each year, of which 85% come from developing countries, and approximately 1.7 million deaths are associated with AKI each year [16].In addition to ischemic kidney injury caused by renal hypoperfusion or major surgery and drug-induced kidney injury, CI-AKI is the third leading cause of hospital-acquired AKI [17]. The risk of CI-AKI is significantly increased in elderly patients and patients with basic renal insufficiency, diabetes, and other adverse factors [18]. The incidence of CI-AKI in patients with chronic kidney disease is up to 40%. Because approximately 13% of hospitalized patients are likely to be permanently dependent on dialysis, CI-AKI is also associated with long-term kidney failure, hospitalization dialysis need, and overall mortality (7-31%) [19]. Among patients recovering from AKI, one-third of them will develop CKD within 2–5 years [20].          

全世界每年约有1330万例患者被诊断为AKI，其中85%来自发展中国家，每年约有170万例死亡与AKI相关[16]。除了肾灌注不足或大手术引起的缺血性肾损伤和药物性肾损伤外，CI-AKI是医院获得性AKI的第三大病因[17]。老年患者和有基础性肾功能不全、糖尿病和其他不良因素的患者发生CI-AKI的风险显著增加[18]。慢性肾脏病患者CI-AKI的发生率高达40%。由于约13%的住院患者可能长期依赖透析，CI-AKI还与长期肾衰竭、住院透析需求和总死亡率（7-31%）有关[19]。在AKI康复患者中，1/3的患者会在2-5年内发展为CKD [ 20]。

CI-AKI is associated with adverse clinical outcomes such as chronic renal failure and cardiovascular events. Although only 0.06% of patients require renal replacement therapy due to decreased renal function [21, 22], approximately 25–30% of CI-AKI will progress to chronic renal failure [23]; The average length of hospital stay and socio-economic burden of CI-AKI increase by 5–10 times [24].Therefore, CI-AKI is linked to longer hospital stay and higher cost, and has become an important disease affecting the health of patients.         

CI-AKI与慢性肾功能衰竭和心血管事件等不良临床结局有关。虽然只有0.06%的患者因肾功能下降而需要肾脏替代治疗[21,22]，但约25%-30%的CI-AKI会进展为慢性肾功能衰竭[23];CI-AKI的平均住院时间和社会经济负担增加了5-10倍[24]。因此，CI-AKI与更长的住院时间和更高的费用有关，并已成为影响患者健康的重要疾病。

The pathogenesis of CI-AKI is elusive, and several mechanisms, including contrast agents-induced direct effects, indirect effects and the production of reactive oxygen species (ROS), have been unveiled to be involved in the development of CI-AKI [25]. In the direct effects, iodine contrast medium can directly induce cytotoxicity of nephrons, including kidney tubular epithelial cells and endothelial cells, leading to mitochondrial dysfunction, apoptosis, pyroptosis, necrosis, and interstitial inflammation. In the indirect effects, iodine contrast medium can change the renal hemodynamics, thereby resulting in the contraction of renal blood vessels and intramedullary ischemia and hypoxia. On the other hand, iodine contrast medium can cause excessive production of ROS or reduce the activity of antioxidant enzymes to result in increased oxidative stress and inflammatory response, and thereby impairing renal function [26]. In addition, renal medullary hypoxia exacerbates ROS generation, which can lead to mitochondrial oxidative stress and mitochondrial dysfunction [27]. The pathogenesis of CI-AKI is provided in Fig. 1.    

CI-AKI的发病机制尚不清楚，包括造影剂诱导的直接效应、间接效应和活性氧（ROS）的产生在内的多种机制已被揭示参与CI-AKI的发展[25]。在直接作用中，碘造影剂可直接诱导肾单位细胞毒性，包括肾小管上皮细胞和内皮细胞，导致线粒体功能障碍、细胞凋亡、细胞焦亡、坏死和间质炎症。在间接作用中，碘造影剂可以改变肾脏血流动力学，从而导致肾血管收缩和髓内缺血缺氧。另一方面，碘造影剂可引起ROS的过度产生或降低抗氧化酶的活性，导致氧化应激和炎症反应增加，从而损害肾功能[26]。此外，肾髓质缺氧会加剧ROS的产生，从而导致线粒体氧化应激和线粒体功能障碍[27]。CI-AKI的发病机制如图1所示。

Iodine contrast medium have direct cytotoxic effects on renal tubular epithelial cells and vascular endothelial cells, leading to swelling, vacuolation, apoptosis, and eventually necrosis, but the precise mechanisms are not fully understood. When these agents pass through the renal tubules, the water is re-absorbed and the contrast agents are concentrated, so the osmotic pressure and viscosity of renal tubule fluid are increased. The increase of viscosity is more obvious, and the vascular resistance is promoted by viscosity increase, leading to slowed blood flow and enhanced local pressure. Because of the increased viscosity, these agents are retained in renal tubule fluid and further result in direct cytotoxicity, thereby affecting mitochondrial enzyme activity and causing abnormal energy metabolism, cell calcium reduction, DNA breakage, mitochondrial dysfunction, and eventually cell apoptosis [28]. Mccullough et al. [29]pointed out that the highly permeable environment induced by the accumulated iodine contrast medium plays an important role in cell apoptosis. Zager et al. [30]revealed that the direct cytotoxic effects induced by these contrast agents largely depend on the extent of mitochondrial damage and plasma membrane damage. These necrotic tubular epithelial cells separate from the basement membrane, fall into the urinary lumen, and cause lumen obstruction and increase tubular pressure, which result in a decreased rate of glomerular filtration.    

碘造影剂对肾小管上皮细胞和血管内皮细胞有直接的细胞毒性作用，导致肿胀、空泡化、细胞凋亡，最终坏死，但确切的机制尚不完全清楚。当这些药物通过肾小管时，水被重新吸收，造影剂被浓缩，因此肾小管液的渗透压和粘度增加。粘度增加更明显，粘度增加促进血管阻力，导致血流减慢，局部压力增强。由于粘度增加，这些药物滞留在肾小管液中，进一步导致直接细胞毒性，从而影响线粒体酶活性，导致能量代谢异常、细胞钙减少、DNA断裂、线粒体功能障碍，最终导致细胞凋亡[28]。Mccullough等[29]指出，碘造影剂积累诱导的高渗透性环境在细胞凋亡中起着重要作用。Zager等[30]发现，这些造影剂诱导的直接细胞毒性作用很大程度上取决于线粒体损伤和质膜损伤的程度。这些坏死的肾小管上皮细胞与基底膜分离，落入尿腔，引起管腔阻塞和肾小管压力增加，从而导致肾小球滤过率降低。

The cytotoxic effects of iodine contrast medium on renal tubular epithelial cells are characterized by vacuoles in renal tubular epithelial cells, excessive oxidative stress induced by increased ROS production, mitochondrial dysfunction, and subsequent ATP reduction. Vacuolation of renal tubular epithelial cells is a drug toxicity indicator of iodine contrast medium and a histopathological feature of CI-AKI [31]. Studies have shown that these contrast agents exert cytotoxic effects in vitro, and almost all types of cells, including vascular endothelial cells and renal tubular epithelial cells, present varying degrees of cell damage or apoptosis when exposure to these agents. Through electron microscope, these agents are found to cause vascular endothelial cell injury, shedding, vacuole formation, vascular endothelial barrier destruction, and permeability increase [32]. Huang et al. [33] reported that after iodine contrast medium injecting into rat tail vein, these rats present swollen kidneys, marked area of congestion in the coronal cortical-medullary junction, increased tubular vacuolation and denaturation of renal tubular epithelial cells, many shed cells in the lumen, congested veins, and blurred cell boundaries, thus leading to CI-AKI development. The molecular mechanisms of cytotoxicity of these contrast agents may mainly involve Caspase-3, Caspase-9 and other pathways, which are directly linked to apoptosis signaling, overload intracellular calcium, reduced cell proliferation, and mitochondrial dysfunction [34, 35].

碘造影剂对肾小管上皮细胞的细胞毒性作用以肾小管上皮细胞中的液泡、ROS 产生增加引起的过度氧化应激、线粒体功能障碍和随后的 ATP 降低为特征。肾小管上皮细胞空泡化是碘造影剂的药物毒性指标，也是CI-AKI的组织病理学特征[31]。研究表明，这些造影剂在体外发挥细胞毒性作用，几乎所有类型的细胞，包括血管内皮细胞和肾小管上皮细胞，在暴露于这些造影剂时都会出现不同程度的细胞损伤或凋亡。通过电子显微镜，发现这些药物会引起血管内皮细胞损伤、脱落、液泡形成、血管内皮屏障破坏和通透性增加[32]。Huang等[33]报道，碘造影剂注射到大鼠尾静脉后，这些大鼠出现肾脏肿胀，冠状皮质-髓质交界处有明显的充血区域，肾小管空泡化增加和肾小管上皮细胞变性，管腔内脱落细胞多，静脉充血，细胞边界模糊，从而导致CI-AKI的发展。这些造影剂的细胞毒性的分子机制可能主要涉及半胱天冬酶-3、半胱天冬酶-9等通路，这些通路与细胞凋亡信号传导、细胞内钙超负荷、细胞增殖减少和线粒体功能障碍直接相关[34,35]。

Renal medullary hypoxia caused by iodine contrast medium-imposed hemodynamic alterations is the leading cause of CI-AKI [36]. After intravascular administration of iodine contrast medium, several hemodynamic changes were observed in the kidneys: an initial rapid, transient hemangiectasis and an initial increase in renal blood flow (RBF); the subsequent sustained vasoconstriction, increased renal vascular resistance, and decreased RBF [37]. These hemodynamic alterations induced by iodine contrast medium may be attributed to the regulation of the synthesis and release of renal vasoactive factors [38]. To overcome the lack of oxygen supply induced by these contrast agents, many factors, such as prostaglandin (PG) and nitric oxide (NO), are generated and released to enhance blood flow. However, the direct cytotoxicity of iodine contrast medium to vascular endothelial cells results in an elevation in endothelin and adenosine levels and a decrease in NO and PG expression [39]. Once the balance between these two opposing effects is broken and shifts toward vasoconstriction, it can trigger medullary ischemia and a decline in glomerular filtration rate (GFR) in the kidneys, especially the outer medulla [40]. During ischemia, blood flow in the kidneys will shift from the medulla to the cortex, resulting in more severe medulla hypoxia [41]. Furthermore, iodine contrast medium also cause osmotic diuresis, which enhances fluid discharge and exacerbates hypoxia [42]. Notably, in patients with chronic kidney disease with reduced renal parenchyma, conventional doses of contrast agents can result in enhanced external medullary ischemia [36]. In addition, diabetic nephropathy is pathologically characterized by renal vascular dysfunction, which may trigger increased sensitivity of vasoconstriction induced by contrast agents, leading to an increased risk of CI-AKI [43, 44].

碘造影剂介质强加的血流动力学改变引起的肾髓质缺氧是CI-AKI的主要原因[36]。血管内给予碘造影剂后，在肾脏中观察到几种血流动力学变化：最初的快速、短暂的血液扩张和肾血流量 （RBF） 的初始增加;随后持续血管收缩，肾血管阻力增加，RBF降低[37]。碘造影剂诱导的这些血流动力学改变可能归因于肾脏血管活性因子的合成和释放的调节[38]。为了克服这些造影剂引起的氧气供应不足，会产生和释放许多因素，如前列腺素 （PG） 和一氧化氮 （NO），以增强血液流动。然而，碘造影剂对血管内皮细胞的直接细胞毒性导致内皮素和腺苷水平升高，NO和PG表达降低[39]。一旦这两种相反作用之间的平衡被打破并转向血管收缩，就会引发髓质缺血和肾脏肾小球滤过率（GFR）下降，尤其是髓质外[40]。在缺血期间，肾脏中的血流会从髓质转移到皮质，导致更严重的髓质缺氧[41]。此外，碘造影剂也会引起渗透性利尿，从而增强液体排出并加剧缺氧[42]。值得注意的是，在肾实质减少的慢性肾病患者中，常规剂量的造影剂可导致外髓缺血加剧[36]。此外，糖尿病肾病的病理特征是肾血管功能障碍，这可能引发造影剂诱导的血管收缩敏感性增加，导致CI-AKI风险增加[43,44]。

Mitochondria are important sites for ROS production. During the process of ischemia and hypoxia, the balance of oxidative stress is disrupted, and mitochondria ROS (mtROS) is overproduced, which further causes lipid peroxidation of mitochondrial membrane and cell membrane, mitochondrial DNA damage, pyroptosis, and apoptosis [45]. ROS can also lead to direct cytotoxicity of renal tubular epithelial cells and vascular endothelial cells, and aggravate renal parenchymal hypoxia by inducing endothelial dysfunction, which together lead to a vicious cycle [27]. Damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns(PAMPs) can produce ROS when stimulated [46]. In addition, DAMPs or PAMPs can combine with specific ligands innate immune cells express pattern recognition receptors (PRRs), such as toll-like receptors (TLRs) and NOD-like receptors (NLRs), which can activate some signaling pathways, such as MAPK, and promoting cytokine release. Some of these factors may be involved in CI-AKI [47, 48]. Work from the past decade has documented that iodine contrast medium induce ROS production mainly through the following four pathways [26].

线粒体是产生ROS的重要场所。在缺血缺氧过程中，氧化应激平衡被破坏，线粒体ROS（mtROS）过量产生，进一步引起线粒体膜和细胞膜脂质过氧化、线粒体DNA损伤、细胞焦亡和细胞凋亡[45]。ROS还可导致肾小管上皮细胞和血管内皮细胞的直接细胞毒性，并通过诱导内皮功能障碍加重肾实质缺氧，共同导致恶性循环[27]。损伤相关分子模式（DAMPs）和病原体相关分子模式（PAMPs）在刺激时可产生ROS[46]。此外，DAMPs或PAMPs可以与特定的配体结合，先天免疫细胞表达模式识别受体（PRR），如toll样受体（TLR）和NOD样受体（NLR），可以激活一些信号通路，如MAPK，并促进细胞因子释放。其中一些因素可能与CI-AKI有关[47,48]。过去十年的研究表明，碘造影剂主要通过以下四种途径诱导ROS的产生[26]。

This pathway consists of extracellular signal-associated kinase (ERK), c-JUN N-terminal kinase (JNK), and p38 MAPK. Iodine contrast medium activate the MAPK signaling pathway, as evidenced by activated ERK1, ERK2, JNK1, JNK2, JNK3, p38 MAPK, and ERK5 [49], to induce ROS production and then enhance the activity of Caspase-9 and Caspase-3, thereby contributing to apoptosis [45]. These contrast agents can also lead to cytotoxicity of human renal tubular epithelial HK-2 cells by repressing cell viability and causing severe mitochondrial vacuolar degeneration and karorrhexis [31]. In human embryonic kidney 293T cells, iodine contrast medium are capable of activating the JNK signaling pathway and thus induce ROS production and diminish cell viability. These studies suggest that the MAPK signaling pathway is involved in iodine contrast medium-induced ROS production [50].

该通路由细胞外信号相关激酶 （ERK）、c-JUN N 末端激酶 （JNK） 和 p38 MAPK 组成。碘造影剂激活MAPK信号通路，如激活ERK1、ERK2、JNK1、JNK2、JNK3、p38 MAPK和ERK5[49]，诱导ROS产生，然后增强Caspase-9和Caspase-3的活性，从而促进细胞凋亡[45]。这些造影剂还通过抑制细胞活力并引起严重的线粒体液泡变性和核病，导致人肾小管上皮HK-2细胞的细胞毒性[31]。在人胚胎肾293T细胞中，碘造影剂能够激活JNK信号通路，从而诱导ROS的产生并降低细胞活力。这些研究表明，MAPK信号通路参与碘造影剂诱导的ROS产生[50]。

SIRT1 is a histone deacetylase of nicotinamide adenine dinucleotide (NAD+), which is mainly present in the nucleus [51]. In rat renal tubular epithelial NRK-52E cells, iodine contrast medium can result in increased ROS production and enhanced cell apoptosis by down-regulating SIRT1. Resveratrol attenuates contrast-induced nephrotoxicity in mice by diminishing oxidative stress and apoptosis by activating the SIRT1-PGC-1 Alpha FoxO1 pathway [52].    

SIRT1是烟酰胺腺嘌呤二核苷酸（NAD+）的组蛋白脱乙酰酶，主要存在于细胞核中[51]。在大鼠肾小管上皮NRK-52E细胞中，碘造影剂可通过下调SIRT1导致ROS产生增加和细胞凋亡增强。白藜芦醇通过激活SIRT1-PGC-1 Alpha FoxO1通路减少氧化应激和细胞凋亡，从而减轻造影剂诱导的小鼠肾毒性[52]。

The Rho/ROCK pathway is an important regulator of vascular smooth muscle cell contraction, cell migration, proliferation, and differentiation. In mice, iodine contrast medium enhance the transcriptional activity of nuclear factor-κB (NF-κB), oxidative stress, inflammation, and apoptosis by activating the Rho/ROCK pathway and thus result in impaired renal function [53].    

Rho/ROCK通路是血管平滑肌细胞收缩、细胞迁移、增殖和分化的重要调节因子。在小鼠中，碘造影剂通过激活Rho/ROCK通路增强核因子-κB（NF-κB）的转录活性、氧化应激、炎症和细胞凋亡，从而导致肾功能受损[53]。

In a mouse model of CI-AKI, the Nrf-2/HO-1 pathway is involved in many cellular functions, including mitochondrial oxidative stress, autophagy, and programmed cell death [54]. Nrf-2 attenuates cell injury by inducing transcription of antioxidant enzyme genes, reducing ROS production, and diminishing oxidative stress. After administration of iodine contrast medium, the Nrf-2/HO-1 pathway is activated to produce an adaptive protective response that can mitigate contrast-induced tissue damage, oxidative stress, and apoptosis [55, 56]. In HK-2 cells, sulfamefen, an activator of the Nrf-2, can reduce ROS content and increase cell viability [57].   

在CI-AKI小鼠模型中，Nrf-2/HO-1通路参与许多细胞功能，包括线粒体氧化应激、自噬和程序性细胞死亡[54]。Nrf-2 通过诱导抗氧化酶基因的转录、减少 ROS 的产生和减少氧化应激来减轻细胞损伤。碘造影剂给药后，Nrf-2/HO-1通路被激活以产生适应性保护反应，可以减轻造影剂诱导的组织损伤、氧化应激和细胞凋亡[55,56]。在HK-2细胞中，Nrf-2的激活剂磺胺芬可以降低ROS含量，提高细胞活力[57]。

Collectively, iodine contrast medium can result in decreased blood flow and increased oxygen consumption in the kidney medulla by inducing hemodynamic alterations, and the resulting state of ischemia and hypoxia further enhances ROS production. Meantime, ROS production can be elevated by tubular necrosis or vacuolar degeneration of epithelial cells induced by the osmotic effect of iodine contrast medium [58]. In turn, the excessive production of ROS and the inactivation of NO synthase (NOS) and prostacyclin synthase cause contraction of renal vessels, and further aggravate the ischemia/hypoxia state in renal tissues. The excessive production of ROS also promotes oxidative stress and thus directly leads to dysfunction of renal tubular epithelial cells and endothelial cells [59], which together form a vicious cycle. Furthermore, the peroxynitrite with strong oxidative ability is generated by reaction of the superoxide anion of ROS and NO, which causes a greater damage to vascular endothelial cells [32]. Oxidative stress can also induce endothelial dysfunction and tubular transport dysfunction, resulting in dual effects of tubular oxidative injury and ischemic injury [45]. In addition, ROS-triggered oxidative stress can induce mitochondrial dysfunction, cell apoptosis, lipid peroxidation of biofilm, etc., and can promote the release of endogenous pro-inflammatory cytokines and activate the auto-inflammatory signaling pathways [60].      

总的来说，碘造影剂可以通过诱导血流动力学改变导致肾髓质中的血流量减少和耗氧量增加，由此产生的缺血和缺氧状态进一步增强了 ROS 的产生。同时，碘造影剂的渗透作用诱导的上皮细胞的肾小管坏死或液泡变性可增加ROS的产生[58]。反过来，ROS的过量产生以及NO合酶（NOS）和前列环素合酶的失活会引起肾血管收缩，并进一步加重肾组织的缺血/缺氧状态。ROS的过量产生也会促进氧化应激，从而直接导致肾小管上皮细胞和内皮细胞的功能障碍[59]，共同形成恶性循环。此外，ROS和NO的超氧阴离子反应生成具有较强氧化能力的过氧亚硝酸盐，对血管内皮细胞造成较大损伤[32]。氧化应激还可诱发内皮功能障碍和肾小管转运功能障碍，导致肾小管氧化损伤和缺血性损伤的双重作用[45]。此外，ROS引发的氧化应激可诱导线粒体功能障碍、细胞凋亡、生物膜脂质过氧化等，并能促进内源性促炎细胞因子的释放，激活自身炎症信号通路[60]。

The excessive production of ROS can abate iodine contrast medium-induced antioxidant enzyme activity and thus contributes to renal function impairment [61]. Studies have uncovered that several importantly cellular processes, including apoptosis, pyroptosis, as well as autophagy, and some epigenetic regulators, such as microRNAs (miRNAs), have implicated in the cytotoxicity effects of iodine contrast medium and the induced ROS [62]. The details of molecular mechanism are provided in Table 2.  

ROS的过量产生会降低碘造影剂诱导的抗氧化酶活性，从而导致肾功能损害[61]。研究发现，几个重要的细胞过程，包括细胞凋亡、细胞焦亡和自噬，以及一些表观遗传调节因子，如microRNA（miRNA），都与碘造影剂和诱导的ROS的细胞毒性作用有关[62]。分子机理详见表2。

Apoptosis, a kind of programmed cell death characterised by a series of irreversible intracellular changes, can be caused by the activation of Caspase family members induced by various pro-apoptotic stimuli, such as endoplasmic reticulum stress and ROS. The morphological manifestations of apoptosis include DNA fragmentation, cytoplasmic condensation, karyopycnosis, karyorrhexis, and apoptotic body formation. However, the cell membrane remains intact during the process of apoptosis, and thus no contents are released, which does not directly cause further inflammatory response [63].

细胞凋亡是一种以一系列不可逆的细胞内变化为特征的程序性细胞死亡，可由各种促凋亡刺激（如内质网应激和ROS）诱导的半胱天冬酶家族成员的激活引起。细胞凋亡的形态表现包括DNA片段化、细胞质凝聚、核脱、核痢和凋亡体形成。然而，细胞膜在细胞凋亡过程中保持完整，因此不会释放任何内容物，这不会直接引起进一步的炎症反应[63]。

Oxidative stress induced by ROS is a potent inducer of apoptosis. Apoptosis is involved in the pathogenesis of CI-AKI. Ca²⁺ overload in renal parenchyma is also found to play a crucial role in CI-AKI through ROS overproduction, p38 MAPK activation, as well as endothelin activation and release [64]. Studies have also shown that oxidative stress caused by ROS accumulation plays an important role in iohexol-induced AKI. Cilnidipine, a blocker of calcium channel, reduces ROS overproduction and alleviates iohexol-induced cell apoptosis, oxidative stress and mitochondrial damage of renal tubular cells in vivo and in vitro by blocking the CaMII-mPTP pathway and inhibiting Ca²⁺overload [65].    

ROS诱导的氧化应激是细胞凋亡的有效诱导剂。细胞凋亡参与CI-AKI的发病机制。还发现肾实质中的钙 ²⁺ 超载通过ROS过量产生、p38 MAPK激活以及内皮素激活和释放在CI-AKI中起关键作用[64]。研究还表明，ROS积累引起的氧化应激在碘海醇诱导的AKI中起着重要作用。西尼地平是一种钙通道阻断剂，通过阻断CaMII-mPTP通路和抑制Ca ²⁺ 过载，在体内和体外减少ROS过量产生，并减轻碘海醇诱导的肾小管细胞凋亡、氧化应激和线粒体损伤[65]。

Pyroptosis, an inflammatory kind of cell death, is an important natural immune response characterized by cell swelling, cell membrane rupture, and the release of cell contents. Pro-inflammatory response is the most distinct and important characteristic that distinguishes it from apoptosis. Iodine contrast medium can strongly enhance host immune response and the release of inflammatory cytokines by inducing the destruction of tubular epithelial cell barrier as well as the injury and necrosis of endothelial cells. The NOD-like receptor pyrin protein 3 (NLRP3) inflammasome has been identified as a crucial regulator of inflammation. As a key component of innate immunity, the NLRP3 inflammasome plays an essential role in the immune response [66]. The NLRP3 inflammasome can be activated by various stimuli, including K+efflux, mitochondrial ROS production, cathepsin release, as well as mitochondrial DNA and cardiolipin release [67]. In the kidney, this inflammasome can be activated by ROS [68]. Excessive ROS production induced by contrast agents is considered to be one of the key molecules in activating the NLRP3 inflammasome. In the resting state, the binding of thioredoxin (TXNIP) and thioredoxin (TRX) can maintain the dynamic balance of oxidation and antioxidant in the body. When ROS activation, TXNIP dissociates from TRX and then binds to the NLRP3 inflammasome, which further participates in oxidative stress and inflammation [69].

细胞焦亡是一种炎症性细胞死亡，是一种重要的自然免疫反应，其特征是细胞肿胀、细胞膜破裂和细胞内容物释放。促炎反应是区别于细胞凋亡的最明显和最重要的特征。碘造影剂可通过诱导肾小管上皮细胞屏障的破坏以及内皮细胞的损伤和坏死，强烈增强宿主免疫反应和炎性细胞因子的释放。NOD 样受体 pyrin 蛋白 3 （NLRP3） 炎症小体已被确定为炎症的关键调节因子。NLRP3炎症小体作为先天免疫的关键组成部分，在免疫应答中起着至关重要的作用[66]。NLRP3炎症小体可被多种刺激激活，包括K+ 外排、线粒体ROS产生、组织蛋白酶释放以及线粒体DNA和心磷脂释放[67]。在肾脏中，这种炎症小体可以被ROS激活[68]。造影剂诱导的过量ROS产生被认为是激活NLRP3炎症小体的关键分子之一。在静息状态下，硫氧还蛋白（TXNIP）和硫氧还蛋白（TRX）的结合可以维持体内氧化和抗氧化的动态平衡。当ROS激活时，TXNIP与TRX解离，然后与NLRP3炎症小体结合，NLRP3炎症小体进一步参与氧化应激和炎症[69]。

The classical NLRP3-Caspase-1-GSDMD inflammatory pathway plays a critical role in CI-AKI. Using in vivo and in vitro experiments, αKlotho, a protein with anti-inflammatory and antioxidant properties, alleviates contrast agents-induced pyroptosis by diminishing the release of GSDMD and IL-1β by significantly suppressing the activation of the NLRP3 inflammasome [70]. Chen et al. [71]uncovered that contrast agents cause kidney injury, up-regulate the protein expression of Caspase-1, NLRP3, ASC and GSDMD, and promote the release of IL-1β, IL-18 and lactate dehydrogenase (LDH), indicating that the classical NLRP3-Caspase-1-GSDMD pathway is implicated in CI-AKI pathogenesis.

经典的NLRP3-Caspase-1-GSDMD炎症通路在CI-AKI中起着关键作用。通过体内和体外实验，αKlotho是一种具有抗炎和抗氧化特性的蛋白质，通过显著抑制NLRP3炎症小体的激活来减少GSDMD和IL-1β的释放，从而减轻造影剂诱导的焦亡[70]。Chen等[ 71]发现造影剂可引起肾损伤，上调Caspase-1、NLRP3、ASC和GSDMD的蛋白表达，并促进IL-1β、IL-18和乳酸脱氢酶（LDH）的释放，表明经典的NLRP3-Caspase-1-GSDMD通路与CI-AKI发病机制有关。   

In non-classical pyroptotic pathway, LPS enters the cytoplasm via transfection or infection and then activates Caspase-4, Caspase-5, and Caspase-11. Activated Caspase-4, Caspase-5, and Caspase-11 disrupt cell function and induce pyroptosis by forming pores in cell membrane by producing N-terminal p30 structure via GSDMD dissociation [72]. Zhang et al. [73] found that in contrast agents-induced AKI, inflammatory factors Caspase-4, Caspase-5, and Caspase-11 can mediate pyroptosis of renal tubular epithelial cells, leading to the occurrence of CI-AKI.

在非经典焦亡途径中，LPS 通过转染或感染进入细胞质，然后激活 Caspase-4、Caspase-5 和 Caspase-11。活化的Caspase-4、Caspase-5和Caspase-11通过GSDMD解离产生N端p30结构，在细胞膜上形成孔隙，从而破坏细胞功能并诱导细胞焦亡[72]。Zhang等[ 73]发现，在造影剂诱导的AKI中，炎症因子Caspase-4、Caspase-5和Caspase-11可介导肾小管上皮细胞的焦亡，导致CI-AKI的发生。

Autophagy supplies energy for cells, maintains self-repair ability and cell homeostasis, as well as removes defective protein molecules and organelles in cells. Autophagy is divided into three types: macroautophagy, microautophagy, and chaperon-mediated autophagy. Mitophagy is a unique process in which autophagosomes specifically swallow and degrade damaged mitochondria. Mitophagy is a mechanism for repairing damaged mitochondria, and its core function is to specifically clear damaged mitochondria and to control the number of mitochondria [74]. Mitochondria are the main source of ROS and the primary organelles for energy production and oxidative stress. Because of ischemia and toxic drug exposure, abnormal mitochondrial morphology and mitochondrial DNA mutations are found in AKI [75]. Damaged mitochondria will lead to the release of ROS and Cyt C, and subsequently induce apoptosis. Mitophagy is a method for the selective removal of damaged mitochondria, and it can protect cells from damage induced by excessive ROS [76]. These contrast agents can stimulate the renal tubular epithelial cells to produce excessive ROS and thus induce mitophagy [77]. Mitophagy is a selective autophagy mechanism that controls mitochondrial mass and mitochondrial ROS (mtROS) content through the degradation of damaged mitochondria. Studies have demonstrated that in CI-AKI, contrast agents can lead to mitochondrial damage and increased mitophagy by destroying the antioxidant defense mechanism, and mitophagy has a protective effect on the apoptosis of renal tubular epithelial cells [78]. Lin et al. [79] found that iohexol can cause mitochondrial damage in renal tubular epithelial cells in CI-AKI mice, thereby inducing the excessive production of mtROS and the activation of the NLRP3 inflammasome. The Pink1/Parkin pathway-mediated mitophagy can repair damaged mitochondria and attenuate the apoptosis of renal tubular epithelial cells and kidney injury in CI-AKI by reducing the production of mtROS and inhibiting the activation of the NLRP3 inflammasome.

自噬为细胞提供能量，维持自我修复能力和细胞稳态，并去除细胞中有缺陷的蛋白质分子和细胞器。自噬分为三种类型：大自噬、微自噬和伴侣介导的自噬。线粒体自噬是一种独特的过程，其中自噬体特异性地吞咽和降解受损的线粒体。线粒体自噬是一种修复受损线粒体的机制，其核心功能是特异性清除受损的线粒体并控制线粒体的数量[ 74]。线粒体是ROS的主要来源，也是能量产生和氧化应激的主要细胞器。由于缺血和有毒药物暴露，AKI患者可发现线粒体形态异常和线粒体DNA突变[75]。受损的线粒体会导致ROS和Cyt C的释放，随后诱导细胞凋亡。线粒体自噬是一种选择性去除受损线粒体的方法，它可以保护细胞免受过度ROS诱导的损伤[76]。这些造影剂可以刺激肾小管上皮细胞产生过量的ROS，从而诱导线粒体自噬[77]。线粒体自噬是一种选择性自噬机制，通过降解受损线粒体来控制线粒体质量和线粒体 ROS （mtROS） 含量。研究表明，在CI-AKI中，造影剂可以通过破坏抗氧化防御机制导致线粒体损伤和线粒体自噬增加，线粒体自噬对肾小管上皮细胞凋亡具有保护作用[78]。Lin 等人。[ 79] 发现碘己醇可引起 CI-AKI 小鼠肾小管上皮细胞的线粒体损伤，从而诱导 mtROS 的过量产生和 NLRP3 炎症小体的激活。Pink1/Parkin 通路介导的线粒体自噬可以通过减少 mtROS 的产生和抑制 NLRP3 炎症小体的激活来修复受损的线粒体并减弱肾小管上皮细胞的凋亡和肾损伤。   

Activation of autophagy can reduce the apoptosis of renal tubular epithelial cells induced by contrast agents, which may be related to the reduction of oxidative stress. Yang et al. [80]found that damaged mitochondria induced by contrast agents are the main source of ROS. The immunomodulator rapamycin reduces the apoptosis of renal tubular epithelial cells and protects against CI-AKI by up-regulating Parkin expression, enhancing mitophagy, alleviating mitochondrial damage and oxidative stress caused by ROS overproduction. In addition, melatonin can significantly mitigate renal toxicity biomarkers and kidney damage by repressing oxidative stress, the NLRP3 inflammasome activation, and apoptosis in CI-AKI by activating autophagy [81]. Recent work has highlighted that inhibition of autophagy can aggravate CI-AKI. Gang Jee Ko and colleagues [82] pointed out that autophagy inhibition by 3-MA aggravates the apoptosis of renal tubule epithelial cells in CI-AKI rats, enhances the oxidative stress caused by contrast agents, and aggravates the kidney damage induced by contrast agents.

自噬的激活可以减少造影剂诱导的肾小管上皮细胞凋亡，这可能与氧化应激的减少有关。Yang等[ 80]发现造影剂诱导的受损线粒体是ROS的主要来源。免疫调节剂雷帕霉素通过上调Parkin表达、增强线粒体自噬、减轻线粒体损伤和ROS过量产生引起的氧化应激来减少肾小管上皮细胞的凋亡，并防止CI-AKI。此外，褪黑激素可以通过抑制氧化应激、NLRP3炎症小体激活和CI-AKI的凋亡来显著减轻肾毒性生物标志物和肾脏损伤[81]。最近的研究强调，抑制自噬会加重CI-AKI。Gang Jee Ko及其同事[82]指出，3-MA抑制自噬会加重CI-AKI大鼠肾小管上皮细胞的凋亡，增强造影剂引起的氧化应激，加重造影剂诱导的肾脏损伤。

MicroRNAs (miRNAs) are a class of non-coding, single-stranded RNA molecules with a length of about 22 nucleotides encoded by endogenous genes, which are involved in the regulation of post-transcriptional gene expression [83]. More than 1,000 miRNAs have been identified in various diseases, including CI-AKI [84]. Gutiérrez Escolano et al. [85]performed the earliest study on miRNAs in CI-AKI, and found 17 kinds of differentially expressed miRNAs in kidney tissues through microarray analysis. Liu et al. [86] found that 19 significantly up-regulated and 22 significantly down-regulated miRNAs in the kidneys of CI-AKI rat model.

MicroRNA（miRNA）是一类非编码的单链RNA分子，其长度约为22个核苷酸，由内源性基因编码，参与转录后基因表达的调控[83]。在包括CI-AKI在内的各种疾病中，已经鉴定出1000多种miRNA[84]。Gutiérrez Escolano等[ 85]对CI-AKI中的miRNA进行了最早的研究，通过微阵列分析发现了17种在肾组织中差异表达的miRNA。Liu等[ 86]发现CI-AKI大鼠模型肾脏中miRNA有19个显著上调，22个miRNA显著下调。

A series of reports using in vitro cellular experimental and in vivo animal models of CI-AKI have shown MiRNA can regulate downstream gene to influence ICM-induced apoptosis, pyroptosis, and autophagy. As an example, miR-188 is significantly upregulated in both CI-AKI rats and contrast agents-induced HK-2 cells, and the overexpression of miR-188 significantly regulates SRSF7 to promote apoptosis of renal tubular epithelial cells [87]. Niu et al. [88]confirmed that miR-429 up-regulation induced by iodixanol could target PDCD4 to inhibit NF-κB signalling pathway and thus attenuates apoptosis to alleviate CI-AKI. Documents had also unveiled that the expression of miR-30e-5p is up-regulated in CI-AKI, and overexpressed miR-30e-5p represses autophagy and promotes apoptosis by reducing the level of one target gene - Beclin1(autophagy associated protein), thereby contributing to CI-AKI [89]. In miniature pigs, miR-30c up-regulation induced by iohexol could alleviates CI-AKI renal injury through diminishing pyroptosis via inhibiting the activation of the NLRP3 inflammasome [90].    

使用CI-AKI的体外细胞实验和体内动物模型的一系列报告表明，MiRNA可以调节下游基因，以影响ICM诱导的细胞凋亡、细胞焦亡和自噬。例如，miR-188在CI-AKI大鼠和造影剂诱导的HK-2细胞中均显著上调，miR-188的过表达显著调节SRSF7，促进肾小管上皮细胞凋亡[87]。Niu等[ 88]证实，碘克沙醇诱导的miR-429上调可以靶向PDCD4抑制NF-κB信号通路，从而减弱细胞凋亡以缓解CI-AKI。文献还显示，miR-30e-5p的表达在CI-AKI中上调，过表达的miR-30e-5p通过降低一个靶基因Beclin1（自噬相关蛋白）的水平来抑制自噬并促进细胞凋亡，从而促进CI-AKI[89]。在微型猪中，碘海醇诱导的miR-30c上调可以通过抑制NLRP3炎症小体的激活来减少焦亡，从而减轻CI-AKI肾损伤[90]。

In addition, miRNAs can be readily detected in plasma and serum in a remarkably stable form. The expression profiles of circulating miRNAs carry immense potential for their use as novel, noninvasive biomarkers in diagnosing and monitoring human diseases [91]. As an example, compared with healthy controls, plasma levels of miR-188, miR-30a and miR-3e are significantly elevated in patients with CI-AKI, implying the roles of these miRNAs as promising biomarkers for the diagnosis of CI-AKI [92]. Although the study of miRNAs in CI-AKI is still in its infancy, these datas suggest that miRNAs can be used as potential targets for CI-AKI therapy and biomarkers for early diagnosis.          

此外，miRNA可以很容易地在血浆和血清中以非常稳定的形式检测到。循环miRNA的表达谱具有巨大的潜力，可作为诊断和监测人类疾病的新型非侵入性生物标志物[91]。例如，与健康对照组相比，CI-AKI患者的血浆miR-188、miR-30a和miR-3e水平显著升高，这意味着这些miRNA作为CI-AKI诊断的有希望的生物标志物的作用[92]。尽管 CI-AKI 中 miRNA 的研究仍处于起步阶段，但这些数据表明 miRNA 可以用作 CI-AKI 治疗的潜在靶点和早期诊断的生物标志物。

The risk of developing CI-AKI depends on factors related to the patient, the type, dose and the route of administration of ICM, and the medication. The details of risk factors of CI-AKI are as follows in Table 3.        

发生CI-AKI的风险取决于与患者、ICM的类型、剂量和给药途径以及药物相关的因素。CI-AKI的危险因素详见表3。

The correlation between age and CI-AKI is still unclear. The 2019 ACR guidelines [93] stated that patients over the age of 60 need to assess their renal function before receiving ICM. However, the 2018 ESUR [5] did not consider advanced age as a risk factor for CI-AKI. The association between the risk of CI-AKI and advanced age might be due to the fact that patients often experience renal dysfunction or other comorbidities as they age. Therefore, it cannot be confirmed that age is an independent influencing factor for CI-AKI.          

年龄与CI-AKI之间的相关性尚不清楚。2019年ACR指南[ 93]指出，60岁以上的患者在接受ICM之前需要评估其肾功能。然而，2018年ESUR[5]并未将高龄视为CI-AKI的危险因素。CI-AKI风险与高龄之间的关联可能是由于患者随着年龄的增长经常出现肾功能不全或其他合并症。因此，不能确认年龄是CI-AKI的独立影响因素。

Compared with patients with normal kidney function, patients who had CKD before using ICM have a significantly increased risk of developing CI-AKI if they undergo ICM examination. The 2018 ESUR guidelines [5] proposed that eGFR < 45 ml · min− 1 · (1.73 m2) −1 for arterial injection of ICM or eGFR < 30 ml · min− 1 · (1.73 m2) −1 for intravenous injection of ICM as independent risk factors for CI-AKI based on the route of administration of ICM.      

与肾功能正常的患者相比，使用ICM前患有CKD的患者如果接受ICM检查，发生CI-AKI的风险显着增加。2018年ESUR指南[5]提出，根据 ICM 给药途径，eGFR<45 ml·min /1.73m² 用于动脉注射ICM或eGFR < 30 ml·min /1.73m² ，静脉注射 ICM 作为 CI-AKI 的独立危险因素。

Diabetes is a common risk factor for CI-AKI. By evaluating the risk of CI-AKI in patients undergoing coronary angiography or coronary intervention, it was found that the incidence of CI-AKI in patients with diabetes was higher [94]. However, diabetes patients have more diseases, so it is not clear whether diabetes is an independent risk factor for CI-AKI.    

糖尿病是CI-AKI的常见危险因素。通过评估接受冠状动脉造影或冠状动脉介入治疗的患者发生CI-AKI的风险，发现糖尿病患者CI-AKI的发生率更高[94]。然而，糖尿病患者患有更多的疾病，因此尚不清楚糖尿病是否是CI-AKI的独立危险因素。

At present, some studies have found that high serum uric acid levels may be related to the occurrence of CI-AKI. A cohort study involving 1440 patients showed that serum uric acid levels ≥ 8.0 mg/dl were associated with an increased risk of CI-AKI [95].         

 
目前，一些研究发现，血清尿酸水平高可能与CI-AKI的发生有关。一项纳入1440例患者的队列研究显示，血清尿酸水平≥8.0mg/dl与CI-AKI风险增加相关[95]。

Due to the important role of the physicochemical properties of ICM (mainly osmotic concentration and viscosity) in their nephrotoxicity [41]. Multiple clinical trials and meta-analyses have shown no evidence that iso-osmolar ICM are associated with a significantly lower rate of CI-AKI than non-ionic, low-osmolar ICM [96]. However, when ionic, high-osmolar ICM are used, the risk of CI-AKI is increased [97].   

       
由于ICM的理化性质（主要是渗透浓度和粘度）在其肾毒性中的重要作用[41]。多项临床试验和meta分析显示，没有证据表明等渗透ICM的CI-AKI发生率显著低于非离子型、低渗透压ICM[96]。然而，当使用离子、高渗透压ICM时，CI-AKI的风险增加[ 97]。

The nephrotoxic effects of ICM may be proportional to the dosage used, and the use of higher doses of ICM is associated with an increase in the incidence and mortality of CI-AKI [98]. Repeated ICM administration within a short interval (48–72 h) has been shown to increase the risk of CI-AKI [99]. 

         
ICM的肾毒性作用可能与使用的剂量成正比，使用较高剂量的ICM与CI-AKI的发生率和死亡率增加有关[98]。研究表明，在短时间间隔（48-72小时）内重复ICM给药会增加CI-AKI的风险[99]。   

Although the 2018 ESUR Guidelines [5] proposed that arterial injection of ICM has a higher risk of CI-AKI compared to intravenous injection, no prospective RCTs have confirmed this association. The current clinical trial conclusions evaluating the risk of CI-AKI due to different administration routes are inconsistent.  

       
尽管2018年ESUR指南[5]提出，与静脉注射相比，动脉注射ICM的CI-AKI风险更高，但没有前瞻性随机对照试验证实这种关联。目前评估不同给药途径导致的CI-AKI风险的临床试验结论并不一致。

Many frequently prescribed medications, such as nonselective NSAIDs, selective Cox-2 inhibitors, several classes of antimicrobial agents and chemotherapeutic agents have nephrotoxic potential and can induce AKI. The risk of CI-AKI was significantly increased [100], so the 2018 ESUR proposed that the use of nephrotoxic drugs withshould be minimized when clinically possible [8]. 2020 the ACR and National Kidney Foundation (NKF)consensus similarly proposed [6], patients with the combined use of nephrotoxic drugs should detect Scr levels before and after the use of ICM. For patients who have already developed an AKI or an eGFR < 30 ml · min− 1 · (1.73 m2) −1, the use of non-essential nephrotoxic drugs and drugs that can affect kidney function is not recommended within 48 h before and after the use of ICM.     

     
许多常用处方药，如非选择性非甾体抗炎药、选择性 Cox-2 抑制剂、几类抗菌药物和化疗药物，具有肾毒性潜力，可诱发 AKI。CI-AKI的风险显著增加[100]，因此2018年ESUR建议在临床上可能时尽量减少肾毒性药物的使用[8]。2020 年 ACR 和美国国家肾脏基金会 （NKF） 共识类似提出 [ 6]，联合使用肾毒性药物的患者应检测使用 ICM 前后的 Scr 水平。对于已经发生AKI或eGFR的患者<30ml/min/1.73m²，不建议在使用ICM前后48小时内使用非必需的肾毒性药物和可影响肾功能的药物。

Metformin is a clinical first-line antidiabetic drug, and its use combined with ICM has a potential risk of lactic acidosis. However, there are differences between the need to stop metformin, how to restart after the instructions and different guidelines [8].          
二甲双胍是临床一线抗糖尿病药物，与ICM联合使用有乳酸性酸中毒的潜在风险。然而，停用二甲双胍的需要、说明后如何重新开始和不同的指南之间存在差异[ 8]。

Although the incidence of CI-AKI is gradually increasing, effective prevention therapy of CI-AKI are very limited at present. Based on the potential pathogenesis of CI-AKI, the commonly used approaches for prevention and treatment of CI-AKI are as follows in Table 4.   

       
虽然CI-AKI的发病率逐渐增加，但目前CI-AKI的有效预防治疗非常有限。根据CI-AKI的潜在发病机制，CI-AKI的常用防治方法如下表4所示。

‍‍‍‍‍Dilution of concentration, reduction of viscosity, acceleration of excretion, and reduction of retention time of contrast agents

Hydration therapy is currently recognized as an effective measure to prevent CI-AKI, which is the only proven effective preventive strategies as opposed to other pharmacologic interventions none of which is proven effective. It can reduce the risk of CI-AKI by improving renal blood flow, dilute the ICM in the renal tubules, reducing the activation of the renin angiotensin system, and reducing the secretion of antidiuretic hormone. Therefore, both the 2012 KDIGO AKI Clinical Practice guideline [7] and the 2018 EUSR CI-AKI prevention guidelines [8] recommend CI-AKI prevention because of hydration therapy. According to the 2016 Chinese Guidelines for Percutaneous Coronary Intervention, isotonic saline hydration therapy has been used as an effective approach for CI-AKI prevention in patients with moderate to severe chronic kidney disease [101].      

   
水合疗法目前被认为是预防 CI-AKI 的有效措施，与其他药物干预措施都没有被证明有效不同，这是唯一被证明有效的预防策略。它可以通过改善肾血流量、稀释肾小管中的ICM、减少肾素血管紧张素系统的活化和减少抗利尿激素的分泌来降低CI-AKI的风险。因此，2012 年 KDIGO AKI 临床实践指南 [ 7] 和 2018 年 EUSR CI-AKI 预防指南 [ 8] 都建议通过补液疗法预防 CI-AKI。根据2016年《中国经皮冠状动脉介入治疗指南》，等渗盐水补液疗法已被用作中重度慢性肾脏病患者预防CI-AKI的有效方法[101]。

Both intravenous and oral hydration may reduce the risk of CI-AKI. In contrast to intravenous hydration, oral hydration prevents CI-AKI due to difficulty in monitoring or controlling hydration speed, the 2018 EUSR guidelines [8] does not recommend the use of oral hydration as the preferred or sole prevention strategy for CI-AKI and does not limit oral hydration in addition to the preferred intravenous hydration. 

         
静脉补液和口服补液均可降低 CI-AKI 的风险。与静脉补液相比，口服补液可预防CI-AKI由于难以监测或控制补液速度，2018年EUSR指南[8]不建议将口服补液作为CI-AKI的首选或唯一预防策略，并且除了首选的静脉补液外，不限制口服补液。

Saline (0.9% NaCl) and bicarbonate, sodium solution (1.4% or 154 mmol/L NaHCO₃) are the most studied intravenous hydrated solutions. But saline and sodium bicarbonate solutions have not uniformly prevented the differences in the effectiveness of CI-AKI. The recent PRESERVE trial studies [102] demonstrated that intravenous sodium bicarbonate versus intravenous sodium chloride had no significant benefit in preventing death, need for dialysis or sustained decline in renal function or CI-AKI in high-risk patients undergoing angiography. Therefore, the intravenous injection of hydration of bicarbonate has similar effectiveness with the hydration of normal saline, but we should consider the high cost of bicarbonate solution and the possibility of alkalosis, so as to select appropriate hydration crystals for patients.    

     
生理盐水（0.9%NaCl）和碳酸氢盐钠溶液（1.4%或154 mmol/L NaHCO₃）是研究最多的静脉水合溶液。但生理盐水和碳酸氢钠溶液并不能一致地防止CI-AKI有效性的差异。最近的 PRESERVE 试验研究 [ 102] 表明，在接受血管造影的高危患者中，静脉注射碳酸氢钠与静脉注射氯化钠在预防死亡、需要透析或肾功能或 CI-AKI 持续下降方面没有显著益处。因此，静脉注射碳酸氢盐水合与生理盐水水合效果相似，但应考虑到碳酸氢盐溶液成本高和碱中毒的可能性，以便为患者选择合适的水合晶体。

At present, there is no consensus on the optimal hydration regimen (speed, volume, time, etc.). Due to the differences in the risk of CI-AKI and hydration conditions between inpatients and outpatients, individualized adjustments should be made during hydration [8].   

       
目前，对最佳补水方案（速度、体积、时间等）尚未达成共识。由于住院患者和门诊患者CI-AKI的风险和补液条件存在差异，因此在补液期间应进行个体化调整[8]。

As previously discussed, ICM administration could cause an increase of ROS production in vasa recta and tubule cells and consequently induces apoptosis, pyroptosis and autophagy activation. Several compounds with antioxidant properties have been investigated including N-acetylcysteine (NAC), statins, and Vitamin C.       

   
如前所述，ICM给药可导致直肠血管和肾小管细胞中ROS的产生增加，从而诱导细胞凋亡，细胞焦亡和自噬活化。已经研究了几种具有抗氧化特性的化合物，包括 N-乙酰半胱氨酸 （NAC）、他汀类药物和维生素 C。

For instance, these purposes can be achieved by the use of the anti-oxidant NAC. NAC was the direct scavenger of free radicals and is thought to have a protective effect on CI-AKI by reducing ROS production, improving blood flow and dilating blood vessels through NO-mediated pathways [103]. Heyman et al. [27]showed that the anti-oxidant NAC could prevent and treat CI-AKI by reducing ROS production and attenuating oxidative stress and inflammatory response.     

     
例如，这些目的可以通过使用抗氧化剂NAC来实现。NAC是自由基的直接清除剂，被认为通过NO介导的途径减少ROS的产生，改善血流和扩张血管，对CI-AKI具有保护作用[103]。Heyman等[27]表明，抗氧化剂NAC可以通过减少ROS的产生和减弱氧化应激和炎症反应来预防和治疗CI-AKI。

However, recent RCTs or meta-analyses did not show a preventive effect of NAC against coronary or peripheral angiography [104] or CI-AKI [105] for in patients undergoing enhanced CT. The recent PRESERVE trial studies [102] also showed that in patients at high risk of renal disease undergoing angiography, oral NAC did not reduce from death, requiring dialysis, persistent renal function decline after 90 d, or the risk of developing CI-AKI. The effectiveness of the NAC in preventing CI-AKI remains undefined.      

   
然而，最近的随机对照试验或荟萃分析并未显示NAC对接受增强CT的患者的冠状动脉或外周血管造影[104]或CI-AKI [105]的预防作用。最近的 PRESERVE 试验研究 [ 102] 也表明，在接受血管造影的肾病高危患者中，口服 NAC 不会因死亡、需要透析、90 d 后肾功能持续下降或发生 CI-AKI 的风险而降低。NAC 在预防 CI-AKI 方面的有效性仍未确定。

Statins, suppressors of hydroxymethylglutaryl coenzyme A, are recently very popular drugs for CI-AKI prevention. Statins can alleviate kidney injury by reducing the formation of local oxygen free radicals and renal ischemia/hypoxia state, thereby reducing the risk of CI-AKI. Moreover, studies have shown that statin therapy can effectively reduce contrast-induced AKI [106].Despite many positive results, it is difficult to make a generally recommended [107] for statins, as these studied patients were cardiac and used multiple statins and standard hydration regimens, eGFR < 45 ml · min− 1 (1.73 m2) −1 patients were not included and most patients undergoing coronary angiography or coronary intervention were already on statins for a long time, these confounding factors contributed to uncertainty in results [108]. Therefore, although short-term high-dose statins may be potentially preventive, they is not recommended to prevent CI-AKI in the absence of other indications [8].    

     
他汀类药物是羟甲基戊二酰辅酶A的抑制剂，是最近非常流行的CI-AKI预防药物。他汀类药物可以通过减少局部氧自由基的形成和肾缺血/缺氧状态来缓解肾损伤，从而降低CI-AKI的风险。此外，研究表明，他汀类药物治疗可有效减少造影剂诱发的AKI[106]。尽管有许多积极的结果，但很难对他汀类药物做出普遍推荐[107]，因为这些研究的患者是心脏患者，并且使用了多种他汀类药物和标准补液方案，eGFR<45ml·min/1.73m ² 患者未被纳入，大多数接受冠状动脉造影或冠状动脉介入治疗的患者已经长期服用他汀类药物，这些混杂因素导致了结果的不确定性[108]。因此，尽管短期大剂量他汀类药物可能具有预防作用，但在没有其他适应证的情况下，不推荐用于预防CI-AKI[8]。

SGLT2i are new generation of hypoglycemic drugs used in the treatment of patients with diabetes mellitus type 2 (T2DM). These inhibitors function by specifically blocking the reabsorption of glucose in the renal tubules, leading to increased glucose excretion and lower blood glucose levels [9, 109]. Emerging data suggested that SGLT2i might prevent CI-AKI through mechanisms not directly related to glucose-lowering, such as anti-inflammatory, and anti-oxidative, thus potentially preventing and attenuating some CI-AKI pathological pathways [110, 111]. Huang. et al. [112] investigated that dapagliflozin(one of the SGLT2i)may ameliorate CI-AKI. On the cell and a rat model established by iohexol, it was clear that dapagliflozin significantly reduced hypoxic injury, apoptosis and kidney histopathological damages by attenuating the HIF-1 alfa/human epididymis protein (HE4)/nuclear factor kappa B (NF-kB) signaling pathway.Moreover, a latest research has shown that the potential protective effect of SGLT2i against CI-AKI in patients with diabetes [113]. Despite some positive results, a very limited body of evidence has focused on the potential link between CI-AKI and SGLT2i therapy. Therefore, although SGLT2i may be potentially preventive, there is not recommended to prevent CI-AKI in the absence of other indications such as T2DM.          
SGLT2i是用于治疗2型糖尿病（T2DM）患者的新一代降糖药。这些抑制剂通过特异性阻断肾小管中葡萄糖的重吸收起作用，导致葡萄糖排泄增加和血糖水平降低[9,109]。新出现的数据表明，SGLT2i可能通过与降糖没有直接关系的机制（如抗炎和抗氧化）预防CI-AKI，从而潜在地预防和减弱一些CI-AKI病理途径[110,111]。黄等[ 112] 研究了达格列净（SGLT2i 之一）可改善 CI-AKI。在碘海醇建立的细胞和大鼠模型上，很明显，达格列净通过减弱 HIF-1 α/人附睾蛋白 （HE4）/核因子 κB （NF-kB） 信号通路显着减少缺氧损伤、细胞凋亡和肾脏组织病理学损伤。此外，一项最新研究表明，SGLT2i对糖尿病患者CI-AKI的潜在保护作用[113]。尽管取得了一些积极的结果，但非常有限的证据集中在CI-AKI和SGLT2i治疗之间的潜在联系上。因此，尽管 SGLT2i 可能具有潜在的预防作用，但在没有其他适应证（如 T2DM）的情况下，不建议预防 CI-AKI。 

Due to the antioxidant properties of Vitamin C, its efficacy in the prevention of oxidative stress-associated diseases has been studied extensively. Vitamin C is a safe, well-tolerated, and readily available antioxidant. Some studies have reported that Vitamin C has a preventive effect on CI-AKI [114]. Some meta-analysis also proved that Vitamin C combined with normal saline can significantly reduce the risk of CI-AKI [115]. However, most RCTs, studies or meta-analyses have not demonstrated that Vitamin C reduces the risk of CI-AKI in patients who received coronary CKD angiography [105]. Vitamin C may have a potential and a preventive effect for CI-AKI, but it still needs to be confirmed by clinical studies.     

     
由于维生素C的抗氧化特性，其在预防氧化应激相关疾病方面的功效已被广泛研究。维生素 C 是一种安全、耐受性良好且易于获得的抗氧化剂。一些研究报道，维生素C对CI-AKI有预防作用[114]。一些荟萃分析也证明，维生素C与生理盐水联合使用可显著降低CI-AKI的风险[115]。然而，大多数随机对照试验、研究或meta分析并未证明维生素C可降低接受冠状动脉CKD血管造影的患者发生CI-AKI的风险[ 105]。维生素C可能对CI-AKI具有潜在的预防作用，但仍需通过临床研究证实。

Adenosine is a vasoconstrictive nucleoside of the kidney, and contrast agents can activate adenosine receptors to cause hemodynamic changes in the kidney, thereby leading to CI-AKI. Theophylline, an adenosine receptor antagonist, is capable of significantly reducing the incidence of CI-AKI and the level of creatinine [116]. However, there are uncertain results regarding the effects of theophylline on CI-AKI [117, 118], nor should theophylline alone be recommended to reduce the risk of CI-AKI.    

     
腺苷是肾脏的血管收缩核苷，造影剂可以激活腺苷受体，引起肾脏的血流动力学变化，从而导致CI-AKI。茶碱是一种腺苷受体拮抗剂，能够显著降低CI-AKI的发生率和肌酐水平[116]。然而，关于茶碱对CI-AKI的影响尚不确定[ 117， 118]，也不应推荐单独使用茶碱来降低CI-AKI的风险。   

In order to avoid the occurrence of CI-AKI, effective prevention is very important. A precise knowledge of the dosage, indication, and use time of contrast agents is thus essential for CI-AKI prevention. The diminishment of the dosage and the avoidance of repeated use of contrast agents in the short term are also very crucial for the reduction of CI-AKI. The risk factors for CI-AKI, such as chronic renal insufficiency, diabetes, advanced age, cardiovascular disease, hemodynamic instability, and some drug combinations should always be noted.       

   
为了避免CI-AKI的发生，有效的预防非常重要。因此，准确了解造影剂的剂量、适应症和使用时间对于预防 CI-AKI 至关重要。在短期内减少剂量和避免重复使用造影剂对于降低CI-AKI也非常重要。应始终注意CI-AKI的危险因素，例如慢性肾功能不全、糖尿病、高龄、心血管疾病、血流动力学不稳定和某些药物组合。

The definition of CI-AKI clearly indicates a causal relationship between the use of ICM and the sharp decline in renal function. The incidence of CI-AKI is lower in the general population, but significantly higher in the high-risk population. Iodine contrast medium can directly induce nephrotoxicity, cause changes in hemodynamic viscosity, and enhance oxidative stress-induced ROS. Apoptosis, pyroptosis, mitophagy, and some epigenetic regulatory factors, such as microRNAs (miRNAs), are associated with the cytotoxic effects of iodine contrast medium and induced ROS. Based on the above mechanism, it may lead to the occurrence and development of CI-AKI. Identifying high-risk comparison subjects and controlling for related risk factors is crucial. Reasonable and effective hydration is a key measure for preventing and treating CI-AKI, and the efficacy of new preventive and therapeutic drugs needs further exploration. The continuous development of medical technology and the deeper understanding of CI-AKI pathogenesis would provide new opportunities to design better interventions for effective prevention and treatment in CI-AKI.   

       
CI-AKI的定义清楚地表明ICM的使用与肾功能急剧下降之间存在因果关系。CI-AKI的发病率在一般人群中较低，但在高危人群中明显较高。碘造影剂可直接诱发肾毒性，引起血流动力学粘度变化，增强氧化应激诱导的ROS。细胞凋亡、细胞焦亡、线粒体自噬和一些表观遗传调节因子，如 microRNA （miRNA），与碘造影剂和诱导的 ROS 的细胞毒性作用有关。基于上述机制，可能导致CI-AKI的发生和发展。识别高风险比较对象并控制相关风险因素至关重要。合理有效的补液是预防和治疗CI-AKI的关键措施，新型预防和治疗药物的疗效有待进一步探索。医疗技术的不断发展和对CI-AKI发病机制的深入理解将为设计更好的干预措施以有效预防和治疗CI-AKI提供新的机会。